Method of making thrombo-resistant non-thrombogenic objects formed from a uniform mixture of a particulate resin and colloidal graphite

ABSTRACT

The disclosure is that of an invention directed to new compositions of matter comprising a mixture of a resin in particulate form and colloidal graphite; and the use of such mixture to form objects of predetermined sizes and shapes, the exposed surfaces of which are strip treated and coated with a cationic surface active agent to make them Heparin-receptive, after which the objects are Heparin-coated to make them thrombo-resistant and non-thrombogenic.

RELATED APPLICATIONS

Applications Ser. Nos. 155 and 156, both filed on Jan. 2, 1979, aredivisions of this application.

THE INVENTION

This invention relates generally to new and useful improvements in theproduction of flexible materials or objects used within the vascularsystems of animate beings and particularly seeks to provide novelcompositions of matter that can be used in the manufacture of suchflexible materials or objects to make them thrombo-resistant andnon-thrombogenic over substantial periods of time.

It is well known that the thrombo-resistant and non-thrombogeniccharacteristics of objects such as catheters, spring guides, etc., areenhanced if they are made from or coated with a fluorinated hydrocarbonsuch as a FEP (hexafluoropropylenetetrafluoroethylene copolymer ) or TFE(tetrafluoroethylene) resin, commercially available as "Teflon" FEP or"Teflon" TFE from Du Pont. Typical examples of such resin-surfacedobjects are described in U.S. Pat Nos. 3,757,768, granted Sept. 11,1973; 3,922,378, granted Nov. 25, 1975; 4,044,765, granted Aug. 30,1977; 4,052,989, granted Oct. 11, 1977; and in this inventor's U.S.patent application Ser. No. 893,964, filed Apr. 6, 1978 and directed toan intracardial electrode.

Even though the thrombo-resistant and non-thrombogenic characteristicsof such objects are adequate for many purposes, it has become apparentthat further improvement is needed, particularly where relatively longretention times may be involved, and this invention is directed to thesolution of that problem.

It is also well known that Heparin, a naturally occurringmucopolysaccharide, is an excellent anti-coagulating agent and has beenused for that purpose for many years.

Accordingly, the problem may be further described as; how can Heparin beapplied and firmly bonded to flexible objects designed for relativelylong time retention within the vascular systems of animate beings?

Heretofore, the direct coating of Heparin on flexible surfaces ofvascular assist devices has not been considered possible because of thebrittle nature of the coatings resulting from the application techniquesthereof known to date.

For example, Gott, et al, in a study reported in Vol. X Trans. Amer.Soc. Artif. Int. Organs, 1964, pages 213-217, discovered that whencolloidal graphite in a liquid plastic binder is coated on rigid metaland plastic surfaces, certain cationic surface active agents firmlyaffix themselves to the graphite particles in a non-reversible manner.The resultant surface may then be treated with an aqueous or salinesolution of Heparin or Heparin-like compound which adheres to thegraphite-cationic base. Although this technique is adapted to rigidsurfaces, it is not effective on flexible surfaces due to the brittlenature of the dual coating.

As another example, Grode, et al, in an article titled "Non-thrombogenicMaterials via a Simple Coating Process" (Vol. XV Trans. Amer. Soc.Artif. Int. Organs, 1969) describes the Heparinization of finely groundtest material by steeping sequentially the test material in a solutionof an oil soluble quaternary ammonium salt and then in an aqueoussolution of Heparin.

In contrast to and as a difference in kind over such earlier knownprocedures, I have discovered that it is possible to createHeparin-receptive surfaces on many types of formed plastic objects,particularly those formed from fluorinated hydrocarbons, through the useof a new composition of matter comprising a mixture of a resin inparticulate form and colloidal graphite. The mixture is processed intoan object of predetermined size and shape by any of the well knownforming techniques such as extrusion, blow or injection molding,pressing and heating, or sheeting. The mixture also is capable of beingformed into threads or yarns which can be braided, woven, knitted orfelted into objects of predetermined size and shape. After an object hasbeen formed from the mixture, its exposed surfaces preferably aretreated with metallic sodium to expose surface areas of the colloidalgraphite particles at or immediately underlying the exposed surfaces ofthe object, then the sodium treated surfaces are cleaned and coated witha cationic surface active agent to make the surfaces Heparin-receptive,after which a coating of Heparin may be applied over the catonic coatingto make the object truly thrombo-resistant and non-thrombogenic.

Although the compositions of matter generally described in the precedingparagraph are particularly directed to those consisting of a mixture ofparticulate fluoropolymers and colloidal graphite, it should beunderstood that for the purposes of this disclosure, other materials inparticulate form, such as halogenated hydrocarbons, polyolefins,polyurethanes, vinyls and silicones may be used in place of thefluropolymers with substantially equivalent results.

Even though the compositions of matter disclosed herein and theirmethods of use are primarily intended to produce flexible objects ofpredetermined sizes and configuration and having Heparin-receptivesurfaces, it should be understood that the techniques involved areequally applicable to rigid objects where Heparin-receptive surfaces arerequired.

Therefore, an object of this invention is to provide novel compositionsof matter, each comprising a mixture of a resin in particulate form andcolloidal graphite, that can be formed into flexible objects ofpredetermined shape and size and then treated to make their exposedsurfaces Heparin-receptive.

Another object of this invention is to provide a method of treating theexposed surfaces of objects formed from such compositions of matter witha surface-stripping or etching agent such as metallic sodium to exposesurface areas of the graphite particles and then coating the strippedsurfaces with a cationic surface active agent to make the surfacesHeparin-receptive, after which a coating of Heparin may be appliedthereto to make them thrombo-resistant and non-thrombogenic.

A further object of this invention is to provide objects manufacturedfrom such compositions of matter that are thrombo-resistant andnon-thrombogenic.

With these and other objects, the nature of which will become apparent,the invention will be more fully understood by reference to thedrawings, the accompanying detailed description and the appended claims.

In the drawings, which are intended to illustrate only one example ofmany objects that can be formed from the compositions of matter and thetechniques herein disclosed:

FIG. 1 is an isometric view of a length of catheter tubing that has beenextruded from a composition of matter prepared in accordance with thisinvention, those graphite particles appearing on the outer surface beingshown in solid black and those located slightly below the surface beingshown in dotted lines. The size of the graphite particles has beenexaggerated in the interest of clarity of illustration;

FIG. 2 is a view similar to FIG. 1 but showing the outer surface of thetube as it appears after having been stripped or etched to expose amultitude of the graphite particles;

FIG. 3 is a transverse section taken along line 3--3 of FIG. 1;

FIG. 4 is a transverse section taken along line 4--4 of FIG. 2; and

FIG. 5 is a view similar to FIG. 4 but showing the tube when finished bythe external sequential applications of cationic surface active agentand Heparin coatings, the internal coatings not being shown.

Referring to the drawings in detail the invention, as illustrated, isembodied in a length of lumen-defining catheter tubing generallyindicated 5 having a predetermined outside diameter and wall thicknessand extruded from a selected resin 6 having colloidal graphite particles7 uniformly distributed therethrough.

The resin-colloidal graphite composition of matter from which the tubing5 is extruded comprises from about 99% to about 70% of a resin in dryparticulate form selected from the group consisting of halogenatedhydrocarbons such as TFE or FEP "Teflon", polyolefins such aspolyethylene and polypropylene, polyurethanes, vinyls such as polyvinylchloride and silicones, and from about 1% to about 30% colloidalgraphite of which the particle sizes may range from about 0.5 micron toabout 3 microns.

The tubing is continuously extruded and passed through a take off unitwhich cools and sets the plastic.

At this stage only random particles of the colloidal graphite areexposed on the surfaces of the tubing as indicated in FIGS. 1 and 3 andit is necessary to strip or etch the surfaces in order to expose amultitude of the graphite particles as indicated in FIGS. 2 and 4, thusformng a base for a subsequently applied coating of a cationic surfaceactive agent which becomes irreversably bonded thereto.

For this purpose, and if the resin of the tubing is a halogenatedhydrocarbon, the tubing from the take off unit is passed through a bathcontaining metallic sodium dispersed with napthalene in a suitablesolvent (such as Ansul 141, a diethyleneglycol dimethylethercommercially available from the Ansul Chemical Company) for a period oftime ranging from about 1 minute to about 10 minutes, depending on theamount of etch desired. Alternately, this procedure may be carried outwith metallic sodium dispersed in liquid ammonia; and in either case thelumen of the tubing may be similarly treated by pumping the sodiumdispersion therethrough.

However, if the resin of the tubing is a polyolefin, a polyurethane, asilicone or a vinyl, the stripping or etching should be effected by ahot oxidizing acid such as a combination of sulfuric and chromic acidsor a combination of sulfuric acid and sodium dichromate, at about110°-170° F. for about 1-45 minutes.

The etched tubing then is cleaned with isopropyl alcohol and washed withde-ionized water and dried to complete its preparation for a coating ofa cationic surface active agent.

The cleaned, washed and dried tubing then is submersed in a 1-10 to1-1000 solution of a suitable cationic surface agent (such as"Zephiran", commercially available from the Sterling Drug Company, orits equivalent) for from about 10 minutes to about 36 hours, dependingon the concentration used, and then dried, thus forming a coating 8. Atthis stage the cationic surface active agent coated tubing is fullyHeparin-receptive and may be coated with Heparin by placing the tubingin an aqueous or saline solution of Heparin for from about 1 minute toabout 120 minutes, depending on the desired thickness of the Heparincoating, and then dried, thus forming an outer coating 9 and renderingthe finished tubing both thrombo-resistant and non-thrombogenic.

The tubing may be made radiopaque if desired by including in theoriginal composition of matter from which the tubing is extruded a smallquantity of any of the well known radiopaquing agents, such as bismuth,barium, lead or tin, none of which will react with the graphiteparticles to degrade the ability of the graphite particles toirreversably accept and bond with the applied coating of the cationicsurface active agent.

It also should be understood that it is possible to use intra-vascularlythe cationic surface active agent coated tubing without the Heparincoating, in which event the exposed coated surfaces of the tubing willpick up the Heparin from the blood endogenously to naturally create athrombo-resistant and non-thrombogenic condition. This same endogenousphenomonon is what adds to the retention life of the Heparin-coatedtubing because as the Heparin coating might otherwise be depleted, itwill continue to be rebuilt naturally.

Further, the tubing is heat-shrinkable when the resin component thereofis a fluoropolymer, such as a FEP or TFE "Teflon", a vinyl or apolyolefin, and can be heat shrunk as a sheathing over and firmly bondedto a flexible inner body, such as a tubular coil spring or braided orwoven catheter tubing, and then surface etched and coated as describedabove to result in a thrombo-resistant non-thrombogenic exteriorsurface.

I claim:
 1. In a method of preparing thrombo-resistant non-thrombogenicobjects, the steps of; preparing a uniform mixture of resin inparticulate form and colloidal graphite; processing said mixture into anobject of predetermined size and configuration and having exposedsurfaces; etching the exposed surfaces of said object to expose surfaceareas of the colloidal graphite particles at or immediately underlyingthe exposed surfaces of said object; cleaning the etched object; coatingthe cleaned object with a cationic surface active agent; and applying acoating of Heparin over the cationic surface active agent coating. 2.The method of claim 1 in which said mixture comprises a major portion ofsaid resin and a minor portion of said colloidal graphite.
 3. The methodof claim 1 in which said mixture comprises from about 99% to about 70%resin and from about 1% to about 30% colloidal graphite; and in whichsaid resin is selected from the group consisting of halogonatedbydrocarbons, polyolefins, polyurethanes, silicones and vinyls.
 4. Themethod of claim 3 in which said resin is a fluoropolymer.
 5. The methodof claim 3 in which said resin is polyethylene.
 6. The method of claim 3in which said resin is polypropylene.
 7. The method of claim 3 in whichsaid resin is polyvinylchloride.
 8. The method of claim 3 in which saidetching is effected by a dispersion of metallic sodium when said resinis a halogenated hydrocarbon.
 9. The method of claim 3 in which saidetching is effected by a hot oxidizing acid selected from the groupconsisting of a combination of sulfuric and chromic acids and acombination of sulfuric acid and sodium dichromate.
 10. In a method ofpreparing Heparin-receptive surfaces on objects intended for retentionin the vascular systems of animate beings, the steps of; preparing auniform mixture of resin in particulate form and colloidal graphite;processing said mixture into an object of predetermined size andconfiguration and having exposed surfaces; etching the exposed surfacesof said object to expose surface areas of the colloidal graphiteparticles at or immediately underlying the exposed surfaces of saidobject; cleaning the etched object; and coating the cleaned object witha cationic surface active agent.
 11. The method of claim 3 in which saidresin is silicone.
 12. In a method of forming a flexible tubular objecthaving thrombo-resistant non-thromboginic exterior surfaces the stepsof; providing a flexible tubular inner body of predetermined length:preparing an outer flexible tubular sheath having a length at leastcoextensive with said inner body and formed from a uniform mixture ofcolloidal graphite and a particulate resin selected from the groupcomprising halogenated hydrocarbons, polyolefins and polyvinyls; fittingsaid outer sheath over said inner body; heat shrinking said outer sheathinto firmly bonded contact with said inner body; etching the exteriorsurfaces of said outer sheath to expose a multitude of particles of saidcolloidal graphite; coating the etched surfaces of said outer sheathwith a cationic surface active agent; and applying a coating of heparinover said cationic surface active agent coating.